Articular cartilage covers the surfaces of all diarthroidal joints. It is a highly hydrated tissue that serves to distribute loads to bone ends and facilitates near frictionless movement. Damage to articular cartilage via trauma or disease is a clinical challenge, as the tissue has limited ability to self-repair, leaving it vulnerable to further degeneration. There are two cell types commonly investigated in the repair of cartilage: chondrocytes and mesenchymal stem cells (MSCs). Chondrocytes are the resident cells in articular cartilage. They produce the extracellular matrix (ECM) and release degradation enzymes to remove aging matrix, maintaining tissue homeostasis. MSCs are multipotent stem cells with the ability to differentiate into multiple cell lineages, including chondrocytes, and reside within the bone marrow. A common surgical strategy used to repair articular cartilage defects, microfracture, utilizes MSCs naturally residing within the bone marrow as a cell source for tissue repair.
Damage to diarthroidal joint tissue, whether due to sports injuries or overuse, causes early-onset osteoarthritis (OA) through multiple mechanisms, including joint instability that causes irregular force distribution and local inflammation. To date, there are no disease-modifying drugs for effective management or treatment of OA. Preventative therapeutics that reduce the progressive cartilage damage after injury could potentially decrease the prevalence of early-onset OA. Local inflammation is a potential therapeutic target, as inflammation results in increased levels of ECM degradation enzymes. Inflammation can be driven by inflammatory cytokines or other stimuli. The inflammatory process triggers increased expression of pro-inflammatory cytokines creating a positive feedback loop and further perturbs joint space homeostasis. The Nuclear factor-κB (NFκB) signaling pathway is a mechanism that controls the transcription of inflammatory cytokines and degradation enzymes implicated in OA. As NFκB is a significant factor in the inflammatory process, inhibition of NFκB activity has been proposed as a potential therapeutic target.
Current available OA therapeutics target pain management and increased mobility at later stages of tissue damage. There remains a significant need to develop disease-modifying agents that reduce OA progression and restore cartilage homeostasis. Patients who may benefit the most from disease-modifying approaches are those with sports-related or overuse injuries which are strong predictors for OA later in life and those undergoing knee surgery. After injury or surgery there is an increase in inflammatory molecules within the joint space that are purported instigators of OA development.
Therefore, there exists a significant need to develop therapeutic strategies to increase the regenerative capacity of cells that could repair cartilage.